Vet Pathol 41:235–243 (2004) Interleukin-1 and Tumor Necrosis Factor- Produce Distinct, Time-dependent Patterns of Acute Arthritis in the Rat Knee1

Abstract. Interleukin-1 (IL-1) and tumor necrosis factor- (TNF-) synergistically induce and sustain arthritis. Two competing hypotheses of arthritis induction are 1) that TNF preferentially mediates inflammation, whereas IL-1 impels bone destruction, or 2) that either cytokine controls the entire process. In this study, these propositions were tested in two experiments by instilling IL-1 or TNF- into one knee of Lewis rats (n 6/ group) to incite arthritis, after which semiquantitative scores for inflammation, bone resorption, osteoclasts, and cartilage integrity were acquired. In the induction study, IL-1 or TNF- (3, 10, or 30 g) was given once to incite arthritis. After 2 days, IL-1 induced significant, dose-dependent increases in inflammation (mild to marked), bone resorption (minimal to moderate), and osteoclasts (minimal to moderate). In contrast, TNF- induced minimal to mild inflammation but had little impact on resorption or osteoclasts. Both IL-1 and TNF (10 g) yielded mild cartilage degeneration. Most lesion scores in TNF-treated rats were significantly lower than those in animals given the same dose of IL-1. In the persistence study, rats were injected once with IL-1 or TNF (10 g) and maintained for 2, 3, or 7 days. IL-1 significantly enhanced inflammation (all 3 days), bone resorption (days 2 and 3), osteoclasts (days 2 and 3), and cartilage matrix loss (days 2 and 3), whereas TNF- augmented inflammation (days 2 and 3) and cartilage degeneration (day 2) but not bone resorption or osteoclasts. Thus, both IL-1 and TNF- can launch inflammation, but IL-1 drives skeletal destruction